ORIGINAL ARTICLE
The Subjective Psychoactive Effects of Oral Dronabinol Studied in a Randomized, Controlled Crossover Clinical Trial for Pain Mohammed A. Issa, MD,*w Sanjeet Narang, MD,*w Robert N. Jamison, PhD,*wz Edward Michna, MD,*w Robert R. Edwards, PhD,*wz David M. Penetar, PhD,wy and Ajay D. Wasan, MD, MSc*wz
Background: Many cannabinoid medications are approved in North America or in phase III trials, such as dronabinol, nabilone, or nabiximols. Little is known about their subjective psychoactive effects when used for pain management. We hypothesized that when used for pain, dronabinol has psychoactive effects in a doseresponse relationship, whose peak effects are comparable with smoking marijuana. Methods: This was a randomized controlled trial of single dose placebo, 10 or 20 mg dronabinol in 30 chronic noncancer pain patients taking opioids and not using marijuana. Participants completed the Addiction Research Center Inventory (ARCI) hourly for 8 hours during 3 monitored sessions. Comparison sample was the ARCI ratings in participants with no pain (N = 20), monitored every 30 minutes after smoking a 1.99% THC (low) and a 3.51% (high strength) marijuana cigarette. Results: The 10 and 20 mg dronabinol doses had significantly elevated scores over time on 4/5 subscales versus placebo (P < 0.05). Average daily morphine use, total pain relief (TOTPAR), age, sex, and baseline pain level were not significant covariates. ARCI peak effects at 2 hours were similar to peak effects of smoked marijuana at 30 minutes (P = 0.80, 10 mg = low strength, 20 mg = high strength). Conclusions: In pain patients, oral dronabinol has similar psychoactive effects to smoking marijuana. This risk must be considered in any decision to prescribe cannabinoid medications for pain. Key Words: cannabinoid, dronabinol, abuse potential, addiction, marijuana
(Clin J Pain 2014;30:472–478)
T
he psychoactive properties of cannabis have been recognized since early times, it remains the most widely used illicit drug globally.1 Despite the possible stigma and legal issues associated with its use, Cannabis sativa has been
Received for publication October 14, 2012; revised November 18, 2013; accepted August 2, 2013. From the Departments of *Anesthesiology, Perioperative, and Pain Medicine; zPsychiatry, Brigham and Women’s Hospital; yBehavioral Psychopharmacology Research Laboratory, McLean Hospital; and wHarvard Medical School, Boston, MA. Supported in part by an investigator-initiated grant from Solvay Pharmaceuticals Inc., Marietta, GA and by grants DA 12014 and DA 00343 from the National Institute on Drug Abuse, Rockville, MD. The authors declare no conflict of interest. Reprints: Mohammed A. Issa, MD, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail: drissa80@ gmail.com). Copyright r 2013 by Lippincott Williams & Wilkins
472 | www.clinicalpain.com
widely used as a herbal remedy for the treatment of various conditions such as migraine, spasticity, nausea, and vomiting, as well as a number of other disorders.2 The search for the active ingredients of the plant led to the first identification of its main psychoactive ingredient, D-9-tetrahydrocannabinol (THC),3 and the subsequent development of cannabinoid medications. Several cannabinoid medications are currently FDA approved in the United States or in phase III trials, such as dronabinol, nabilone, or nabiximols. Research into their effects continues to be a field of increasing interest, particularly with regard to their use in a variety of therapeutic areas. Dronabinol is an oral synthetic stereoisomer of THC and is currently approved as an appetite stimulant in patients with HIV/AIDS and as a treatment for chemotherapy-induced nausea and vomiting in patients who failed to respond adequately to conventional antiemetic treatments.4 It has been widely studied for a number of other conditions including multiple sclerosis, Parkinson disease and Huntington disease, and disturbed behavior in Alzheimer disease and Tourette syndrome.5 Another area of study is the use of cannabinoid medications for the treatment of persistent intractable pain. With the discovery of the endocannabinoid system and its involvement with analgesia, recent interest has emerged regarding the pain-modulating effects of cannabinoids and the potential of their synergistic analgesic effect with opioids for pain management.6–12 However, such research has not addressed the existing controversy about the psychoactive effects of medicinal cannabinoids when used for pain management, and whether such effects differ from those of the whole marijuana plant. The primary objective of this study was to evaluate the subjective psychoactive effects of oral dronabinol in chronic pain patients on stable doses of opioids, and compare such effects with placebo and smoked marijuana. The Addiction Research Center Inventory (ARCI), a well-validated and reliable measure to assess the subjective effects of certain classes of psychoactive drugs,13 was used as the primary outcome measure for this study. We hypothesized that when used for pain, dronabinol would have psychoactive effects in a dose-response relationship, whose peak effects are comparable with smoking marijuana.
MATERIALS AND METHODS Trial Design The oral dronabinol study was a multidose, randomized, double-blind, placebo-controlled, crossover trial with 3 drug administration sessions conducted at Brigham and Clin J Pain
Volume 30, Number 6, June 2014
Clin J Pain
Volume 30, Number 6, June 2014
Women’s Hospital in the United States. The comparison sample study cohort with smoked marijuana was a 4-visit, randomized-dosing trial conducted separately at McLean Hospital. The dronabinol cohort permitted quantitative determinations of the subjective psychoactive effects, whereas the smoked marijuana cohort allowed for additional qualitative comparisons.
Participants The studies were reviewed and approved by the Institutional Review Boards at Brigham and Women’s Hospital and McLean Hospital, Boston, MA. All participants provided written informed consent before any study-related procedures were performed and were all compensated for their participation in the studies. For the dronabinol group, subjects were compensated $75 for participation in each session. For the smoked marijuana group, subjects were paid $100 for each of the first three smoking study sessions and $150 for the fourth session. They were given a $100 bonus if they finished all four study sessions. Table 1 summarizes the baseline characteristics of the oral dronabinol sample, which has previously been reported in the publication of the analgesic data.10 Thirty chronic noncancer pain participants on opioid therapy were recruited through Brigham and Women’s Hospital. The
TABLE 1. Patient Demographic and Descriptive Characteristics for the Oral Dronabinol Sample (N = 30)
Variables Age (median) 43.5 (± 11.8; range, 21-67) Sex (% Female) 53.3 Race (% white) 96.7 Pain site (% low back) 66.7 Pain duration (% >5 y) 66.7 Opioid duration (% >2 y) 70 Morphine equivalent 68.1 (SD = 57.2; range, 7.5-228) (oral mg/d) Current opioid medication (% of participants) RTC Methadone 30 Morphine—long-acting 30 Oxycodone—long-acting 16.7 PRN Oxycodone—short-acting 36.7 Morphine—short-acting 16.7 Hydrocodone 6.7 Hydromorphone 6.7 Baseline levels Prestudy Diary (0-10) Pain Intensity 6.9 (± 1.3) Pain Relief 3.9 (± 1.7) Pain Bothersomeness (0-4) 2.7 (± 0.6) Satisfaction Baseline (0-10) 3.7 (± 2.0) Brief Pain Inventory Interference with sleep 6.7 (± 3.2) RAND-36 (0-100) Energy/Fatigue 37.1 (± 20.8) Pain 26.6 (± 15.2) Social Functioning 47.8 (± 24.6) HADS Anxiety 6.7 (± 2.9) Depression 6 (± 3.3) HADS indicates Hospital Anxiety and Depression Scale; PRN, as needed; RAND-36, RAND-36-Health Survey; RTC, return to clinic.
r
2013 Lippincott Williams & Wilkins
Subjective Psychoactive Effects of Oral Dronabinol
ages of participants ranged from 21 to 67 years (median age, 43.5 ± 11.8), 53% were female, and the majority selfidentified as white (96.7%). Most participants (66.7%) reported chronic pain >5 years, and low back pain (66.7%) was the most prevalent. The mean morphine equivalent dose per day was 68.1 mg (range, 7.5 to 228.0 mg). Baseline pain intensity was 6.9/10 (± 1.3). Nineteen participants (63.3%) reported using marijuana in the past, 8 of whom reported using within the past year. All participants were required to abstain from use for 1 month before and during enrollment. Participants were also required to have stable opioid analgesic dose for >6 months and report pain of at least 4 on a 0 to 10 numeric rating scale. They were asked to reschedule their visit if their average pain over the past 24 hours was 11 on the Hospital Anxiety and Depression Scale [HADS]); current substance abuse by selfreport and psychosocial history; and any involvement in active litigation, compensation, or disability issues. The comparison cohort consisted of 20 participants with no pain and their ages ranged from 19 to 30 years old (mean age, 21.7 ± 3). Ninety-five percent reported using marijuana 1.6 ± 0.97 times per week, smoked 15.3 ± 4.2 tobacco cigarettes per day, and drank 9 ± 5.6 alcoholic drinks per week. They all showed normal physical examination, electrocardiogram, and clinical laboratory tests before enrollment. They were all current tobacco smokers (average of 10 to 20 cigarettes daily), had no history of drug or alcohol dependence, and no diagnosis of any psychiatric disorders.14
Interventions The aim of this study was to compare the profile of acute effects on subjective measures of dronabinol at 2 doses (10 and 20 mg capsules) with placebo in patients with chronic pain and smoked marijuana (1.99% and 3.51% D9 THC) in those without chronic pain. At the baseline visit for those with chronic pain, enrollment criteria were verified, informed consent was obtained, a history and physical examination were completed, and baseline questionnaires about the participants’ pain, function, and mood were administered. During the 3 treatment sessions, each participant received identically appearing placebo, 10 or 20 mg dronabinol capsules in 1 of 6 randomly allocated sequences. The randomization scheme was generated by the Investigational Drug Service hospital pharmacy, and both study personnel and participants were blinded until all participants had completed the study. The 3 treatment sessions were separated by a minimum of 3 days between each visit. On arrival, participants were asked to complete the ARCI questionnaire and answer questions about their pain and satisfaction levels. These questionnaires were subsequently administered every hour for 8 hours. A symptom checklist www.clinicalpain.com |
473
Clin J Pain
Issa et al
Volume 30, Number 6, June 2014
FIGURE 1. Research design and schema of the oral dronabinol sample.
was administered at the initial and final visits to assess the occurrence of side effects. At the completion of each treatment session, participants were asked to evaluate the blinding process and record their overall satisfaction with the treatment.
Primary Outcome Measure The primary outcome measure of the study was the ARCI. The ARCI is a true/false 49-item well-known, selfrated, well-validated, and reliable measure that can be used to assess the subjective effects of certain classes of psychoactive drugs.13 Elevated scores on its 5 subscales highly correlate with significant psychoactive effects that may potentially increase the likelihood that a substance will be abused in a vulnerable population: the Morphine-Benzedrine Group (MBG, a measure of euphoria and is considered as the hallmark subjective effect of abused drugs), the Benzedrine Group (BG, a measure of stimulant effects relating to intellectual efficacy and energy), the Pentobarbital-Chlorpromazine-Alcohol Group (PCAG, a measure of apathetic sedation), the Amphetamine Scale (A, a measure of amphetamine-like stimulant effects), and the Lysergic Acid Diethylamide (LSD-specific group, a measure of somatic discomfort and dysphoria). Participants were administered the ARCI by paper-and-pencil every hour in the dronabinol group and electronically using a keypad every 30 minutes in the smoked marijuana group.
Study Procedures A comparison sample of those with no pain who smoked marijuana was chosen to contextualize the findings regarding the psychoactive effects of dronabinol in patients with chronic pain. In other words, it was used to illustrate how the effects of dronabinol might compare to smoked cannabis, on a qualitative level primarily. This was a post hoc comparison and, therefore, would not be able to conclusively determine if there were significant differences between groups. As such, despite the statistical limitations in directly comparing cohorts, it was hypothesized that the comparison group
474 | www.clinicalpain.com
would demonstrate similar psychoactive effects to those with chronic pain taking dronabinol. Study procedures in both cohorts were quite similar, and all data were collected in a monitored laboratory environment at individual sessions over the same period of time in 2 hospitals of the Partners Healthcare System (Brigham and Women’s and McLean Hospitals). The comparison sample was a healthy study population with no pain (n = 20), monitored every 30 minutes with the ARCI for 3 hours after smoking a 1.99% THC (low strength) and a 3.51% THC (high strength) marijuana cigarette in random order, at different study sessions. Smoking sessions lasted for 15 minutes, each through a watercooled inhaler device, and participants were monitored continuously for the next 3 hours after smoking. The study visits were separated by a minimum of 3 days between each visit. Participants were required to abstain from all illicit drugs and alcohol for 72 and 24 hours, respectively, before the study. They could not smoke tobacco or have any caffeine from midnight before each study day. Breath samples to check for alcohol and carbon monoxide, as well as urine samples and blood samples (to test for THC and its metabolites, nicotine, cotinine) were collected when participants arrived to the laboratory. Urine drug tests had to be negative for drugs of abuse excluding THC metabolites, or else study visit was rescheduled. If the urine test was positive for THC metabolites, one of the blood samples was tested for the presence of THC and its metabolites to determine if there has been use within the past 72 hours. For more specific details on the experimental design of the comparison study, including the marijuana challenge session, see Penetar et al.14
Statistical Analysis All data were analyzed with Statistical Package for the Social Services (SPSS v 13.0; Chicago, IL). A repeated measures analysis of covariance (ANCOVA) was used to assess hourly and peak subjective responses on the ARCI scales as a primary measurement of dronabinol subjective effects. This was supplemented by an analysis of variance r
2013 Lippincott Williams & Wilkins
Clin J Pain
Volume 30, Number 6, June 2014
comparison between cohorts and doses at the time of peak psychoactive effects. This was determined by the highest mean of 5 ARCI subscale scores in both the cohorts (t = 2 h for the dronabinol group and t = 30 min for the smoked cannabis group). The Tukey corrections were used for multiple dose comparisons within each ARCI subscale for the ANCOVA and peak effects analyses, as each subscale measures a separate construct. Potential covariates that were included in a sensitivity analysis were: age, sex, race, location, type and duration of pain, average morphine equivalent dose and duration of opioid treatment, baseline pain level, baseline HADS score, previous marijuana use, and total pain relief (TOTPAR) reported over the course of the 8-hour sessions in the chronic pain group (TOTPAR). Statistical significance was set at Pr0.05.
RESULTS Dronabinol Versus Placebo Comparisons A repeated measures analysis found that the 10 and 20 mg dronabinol doses resulted in significant changes, relative to placebo, on 4 of the 5 ARCI subscales over time (Fig. 2). Relative to placebo, dronabinol significantly increased MBG (drug effect: F = 5.5; P < 0.05), PCAG (drug effect: F = 8.0; P < 0.01), and Amphetamine (A) (drug effect: F = 3.3; P < 0.05) scores, and decreased BG (drug effect: F = 3.1; P < 0.05) scores. There were no significant differences between the 10 versus 20 mg doses. The overall trends, however, suggest that the 20 mg dose was
Subjective Psychoactive Effects of Oral Dronabinol
associated with the greatest psychoactive effects. BG scores after dronabinol dose were lowest at 2 hours as compared with placebo, indicating a worsening of intellectual energy. For the other subscales, peak effects of the 2 doses of dronabinol versus placebo were also found at 2 hours (P < 0.05 for MBG, PCAG, A, BG, and LSD). The effects of dose on LSD scores were nonsignificant over time (P > 0.05), but the 10 and 20 mg doses were significantly greater than placebo at 2 hours. In the sensitivity analysis, for each of the 3 treatment conditions (placebo, dronabinol 10 and 20 mg), average daily morphine use equivalents, TOTPAR, age, sex, previous marijuana use, and baseline pain level did not show any significant correlations with ARCI effects on any subscale. In a repeated measures ANCOVA analysis, these factors were not significant univariate predictors of ARCI subscale scores; there was neither significant interaction with dose, nor did they significantly alter the F value of dose as a primary predictor of outcome (Fig. 3). In particular, there was no significant relationship between the level of reported pain relief (TOTPAR) and ARCI subscale scores in correlational or ANCOVA analyses, indicating that dronabinol analgesia was reported by the participants as a phenomenon distinct from its psychoactive effects.
Dronabinol Versus Marijuana Smoking Comparisons Peak psychoactive effects of smoked cannabis were found at 30 minutes after completing the inhaling
FIGURE 2. Hourly Addiction Research Center Inventory (ARCI) subscale scores for dronabinol versus placebo. LSD subscale comparisons nonsignificant (not shown). *P < 0.05; **P < 0.01 versus placebo. BG indicates the Benzedrine Group ; LSD, Lysergic Acid Diethylamide; MBC, Morphine-Benzedrine Group; PCAG, Pentobarbital-Chlorpromazine-Alcohol Group. r
2013 Lippincott Williams & Wilkins
www.clinicalpain.com |
475
Issa et al
Clin J Pain
Volume 30, Number 6, June 2014
FIGURE 3. Comparisons of pain intensity differences (TOTPAR) with 10 and 20 mg dronabinol compared with placebo (P < 0.05 and P < 0.01). There were no significant correlation between TOTPAR and Addiction Research Center Inventory (ARCI) effects for each condition. Error bars: ± 2 SE.
procedure. For 3 of the ARCI subscale scores, there were significant differences between the peak psychoactive effects of oral dronabinol (10 or 20 mg at 2 h) and smoked marijuana (low and high dose at 30 min) as compared with placebo (Fig. 4). PCAG (drug effect: F = 5.4; P < 0.05) and LSD (drug effect: F = 3.3; P < 0.05) scores were significantly increased and BG (drug effect: F = 3.5; P < 0.05)
score was significantly decreased in comparison with oral placebo. However, MBG and Amphetamine (A) score differences were not statistically significant (P > 0.05). Peak psychoactive effects of dronabinol 10 and 20 mg at 2 hours were similar to peak effects of low-strength and high-strength smoked marijuana at 30 minutes in all 5 ARCI subscale scores, and there were no statistically significant differences between them (P > 0.45, Fig. 4). Overall, as reported by the participants on the ARCI, the subjective experiences of taking oral dronabinol or smoking marijuana do not appear to be significantly different than each other.
DISCUSSION
FIGURE 4. Peak psychoactive effects of dronabinol 10 or 20 mg versus low or high dose marijuana cigarettes. P-values are all >0.45 for these comparisons. Error bars: ± 2 SE. BG indicates the Benzedrine Group; LSD, Lysergic Acid Diethylamide; PCAG, Pentobarbital-Chlorpromazine-Alcohol Group.
476 | www.clinicalpain.com
This study attempted to assess the subjective psychoactive effects of the cannabinoid medication, dronabinol, when used in combination with stable opioid dosage for pain management, as compared with placebo and smoked marijuana. Results of the study showed that the subjective effects of 10 and 20 mg dronabinol were consistently and significantly greater than placebo on most ARCI subscales and were equivalent to the psychoactive effects of smoking marijuana, although, as expected, it took longer to reach the same peak effects (2 h with oral dronabinol as compared with 30 min with smoked marijuana). These findings imply that in our laboratory environment, dronabinol caused a “high” similar to smoking marijuana when used for pain management. However, this does not necessarily mean that dronabinol has the same abuse liability as marijuana, and other risk factors for addiction should also be considered before concluding that such a risk exists. For instance, the ARCI does not assess drug likability, which is also an important indicator of drug abuse potential. In addition, the results of previous studies assessing the subjective effects and likelihood for abuse and diversion of dronabinol have differed according to the study setting. Several laboratory studies have shown that the subjective effects of smoked marijuana and oral cannabinoids are highly similar in participants who are regular users of r
2013 Lippincott Williams & Wilkins
Clin J Pain
Volume 30, Number 6, June 2014
marijuana and do not have a diagnosis of chronic pain.15–19 Yet, phase IV drug surveillance observational clinical studies carried out primarily in patients with cancer or HIV/AIDS have reported a low abuse potential of such medications. Moreover, a review by Calhoun et al20 found no evidence of abuse or diversion for dronabinol. The authors noted that marijuana users do not value the psychoactive effects of dronabinol because of its slow and gradual onset of action, weak reinforcing effect, and dysphoric feeling. Similar conclusions were also reached with other cannabinoid medications, such as nabilone and nabiximols, with cases of abuse or diversion being rare and only occurring in a very small proportion of recipients.21,22 It is important to recognize the distinct differences between these laboratory and clinical data as they should be interpreted independently. Our study bridges these gaps to some extent. The present study focuses on the subjective effects of dronabinol in a laboratory-based, randomized, double-blinded, multiple dose, crossover trial in a specific patient population with pain, that is, patients with noncancer pain taking prescription opioids. Our results demonstrate that the subjective effects of dronabinol in a laboratory setting are comparable with smoking marijuana, which potentially applies to other oral cannabinoid medications as well in this environment. These laboratory findings may or may not translate clinically to an increased likelihood of dronabinol abuse and/or diversion in this vulnerable patient population (which requires further study). Aside from these considerations, a special aspect in the case of prescribing cannabinoids for chronic pain is the expectation of long-term use and the possible combination with opioid therapy, which may very well increase the abuse liability of both drugs because of their potentially additive addictive properties. In addition, evidence from the National Household Survey on Drug Abuse suggests that the use of marijuana, especially at a young age, can potentially lead to the future use of other illicit substances.23 In our study, although participants were carefully screened before enrollment, THC was found in 4 of the serum samples of chronic pain participants before receiving placebo, which suggests possible illicit use of marijuana by some participants. Therefore, as substance use disorders are already highly prevalent in the chronic pain population,24–26 potential candidates for cannabinoid therapy should be closely selected, educated about, and monitored.27,28 Another important finding in the study was the insignificant relationship between the level of total reported pain relief (TOTPAR) and ARCI subscale scores. This indicates that the psychoactive properties of dronabinol are independent of its synergistic analgesic effects with opioids (reported previously).10 It was believed from early studies that THC could only produce analgesia at doses that were high enough to cause other behavioral side effects. Noyes et al29 compared single doses of placebo and 5,10,15, and 20 mg of THC in 10 cancer pain participants and found significant analgesia with higher doses but at the expense of significant sedation and mental clouding. The first evidence that the antinociceptive effects of THC could be separated from its adverse behavioral effects was presented in 1994, when Smith et al30 demonstrated that a k-opioid receptor antagonist, nor-binaltorphimine (norBNI), blocked only the antinociceptive effect of THC in rodents without altering other pharmacological or behavioral effects. Our study in humans illustrates this phenomenon of separate r
2013 Lippincott Williams & Wilkins
Subjective Psychoactive Effects of Oral Dronabinol
analgesic and psychoactive properties of cannabinoids in a clinical pain patient population. One could argue that the psychoactive effects of dronabinol were amplified by concomitant oral opioid usage in our pain cohort; however, baseline assessment of the study participants did not reveal any patient reports of significant sedation, confusion, impairment, or other cognitive effects of opioids. Nevertheless, this is a potential confounder to generalizing that dronabinol has significant psychoactive effects comparable with smoking marijuana. There are a number of additional limitations worth mentioning in the design of this study. First, the number of participants in each group was limited, and the dronabinol cohort consisted of a heterogenous sample on various doses of opioids. Although this may reflect a typical clinical pain population, future studies with less variability in opioid type and dosage and longer follow-up period are required. Second, the comparison information was collected historically from a previous study that utilized the same primary outcome measure; therefore, between-study variations may have affected our findings. As observed in the methods, we recognize the statistical limitations in directly comparing the dronabinol and smoked marijuana groups. However, these comparisons are still useful qualitatively to illustrate that the psychoactive effects of dronabinol are clinically meaningful. We cannot conclude that the effects of dronabinol and smoked cannabis are equivalent. In addition, only one measure (namely, the ARCI) was used to compare the acute dose effects of oral dronabinol with smoked marijuana, which is not sufficient to give definitive data on a drug’s abuse potential. Thus, additional data from physiological, psychomotor, and cognitive measures should be collected in future studies to better understand the psychoactive effects and abuse liability of oral dronabinol. Further, urine drug testing was not performed before testing in the dronabinol group. We only assessed possible concurrent drug use with self-report, which is a possible confounder to our results. Finally, we did not have an additional comparison group of chronic pain patients who were not taking opioids for pain, as opioids may share several of the subjective and psychoactive effects noted with cannabinoids.31 Despite these limitations, the results of this preliminary study suggest that in chronic pain patients on opioid therapy, dronabinol has similar psychoactive effects to smoking marijuana. This warrants further large-scale observational studies to assess a potential abuse and/or diversion risk. The subjective psychoactive effects of cannabinoids should be considered in any decision to prescribe these medications for chronic noncancer pain. Moreover, our findings have implications for the analgesic development of all medicinal cannabinoids and indicate that these safety issues should be carefully scrutinized in drug development. We were also able to determine that the psychoactive effects of dronabinol are distinct from their analgesic effects. REFERENCES 1. World Drug Report 2011, Cannabis market. Available at: http://www.unodc.org/documents/data-and-analysis/WDR2011/ The_cannabis_market.pdf. Accessed May 30, 2013. 2. Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers. 2007;4:1614–1648. 3. Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86:1646–1647.
www.clinicalpain.com |
477
Issa et al
4. Solvay Pharmaceuticals Inc. Marinols Prescribing Information, 2006. Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2006/018651s025s026lbl.pdf. Accessed May 9, 2013. 5. RotECoDDEAodais-iAf. Assessment of dronabinol and its stereo-isomers. Available at: http://who.int/medicines/areas/ quality_safety/4.2DronabinolCritReview.pdf. Accessed May 30, 2012. 6. Smith FL, Cichewicz D, Martin ZL, et al. The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol. Pharmacol Biochem Behav. 1998;60:559–566. 7. Cichewicz DL, Martin ZL, Smith FL, et al. Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification. J Pharmacol Exp Ther. 1999;289:859–867. 8. Cichewicz DL, McCarthy EA. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003;304:1010–1015. 9. Cichewicz DL. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. 2004;74:1317–1324. 10. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008;9:254–264. 11. Vigano` D, Rubino T, Parolaro D. Molecular and cellular basis of cannabinoid and opioid interactions. Pharmacol Biochem Behav. 2005;81:360–368. 12. Hohmann AG, Suplita RL. Endocannabinoid mechanisms of pain modulation. AAPS J. 2006;8:E693–E708. 13. Fischman MW, Foltin RW. Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict. 1991;86:1563–1570. 14. Penetar DM, Kouri EM, Gross MM, et al. Transdermal nicotine alters some of marihuana’s effects in male and female volunteers. Drug Alcohol Depend. 2005;79:211–223. 15. Hart CL, Haney M, Vosburg SK, et al. Reinforcing effects of oral Delta9-THC in male marijuana smokers in a laboratory choice procedure. Psychopharmacology (Berl). 2005;181: 237–243. 16. Kirk JM, Doty P, De Wit H. Effects of expectancies on subjective responses to oral delta9-tetrahydrocannabinol. Pharmacol Biochem Behav. 1998;59:287–293. 17. Chait LD, Zacny JP. Reinforcing and subjective effects of oral delta 9-THC and smoked marijuana in humans. Psychopharmacology (Berl). 1992;107:255–262.
478 | www.clinicalpain.com
Clin J Pain
Volume 30, Number 6, June 2014
18. Wachtel SR, ElSohly MA, Ross SA, et al. Comparison of the subjective effects of Delta(9)-tetrahydrocannabinol and marijuana in humans. Psychopharmacology (Berl). 2002; 161:331–339. 19. Hart CL, Ward AS, Haney M, et al. Comparison of smoked marijuana and oral delta(9)-tetrahydrocannabinol in humans. Psychopharmacology (Berl). 2002;164:407–415. 20. Calhoun SR, Galloway GP, Smith DE. Abuse potential of dronabinol (marinol). J Psychoactive Drugs. 1998;30:187–196. 21. Ware MA St, Arnaud-Trempe E. The abuse potential of the synthetic cannabinoid nabilone. Addiction. 2010;105: 494–503. 22. Robson P. Abuse potential and psychoactive effects of d-9tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Expert Opin Drug Saf. 2011;10:675–685. 23. SAMHSA Fact sheet: National Household survey on Drug Abuse, 2011. Available at: http://www.samhsa.gov/ data/NSDUH/2k10NSDUH/2k10Results.htm#5.3. Accessed June 6, 2013. 24. Fishbain DA, Rosomoff HL, Rosomoff RS. Drug abuse, dependence, and addiction in chronic pain patients. Clin J Pain. 1992;8:77–85. 25. Maruta T, Swanson DW, Finlayson RE. Drug abuse and dependency in patients with chronic pain. Mayo Clin Proc. 1979;54:241–244. 26. Ready LB, Sarkis E, Turner JA. Self-reported vs. actual use of medications in chronic pain patients. Pain. 1982;12:285–294. 27. Butler SF, Budman SH, Fernandez K, et al. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain. 2004;112:65–75. 28. Butler SF, Budman SH, Fernandez KC, et al. Development and validation of the Current Opioid Misuse Measure. Pain. 2007;130:144–156. 29. Noyes R, Brunk SF, Baram DA, et al. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol. 1975;15: 139–143. 30. Smith PB, Welch SP, Martin BR. Interactions between delta 9tetrahydrocannabinol and kappa opioids in mice. J Pharmacol Exp Ther. 1994;268:1381–1387. 31. Zacny JP, Gutierrez S. Subjective, psychomotor, and physiological effects profile of hydrocodone/acetaminophen and oxycodone/acetaminophen combination products. Pain Med. 2008;9:433–443.
r
2013 Lippincott Williams & Wilkins
The Subjective Psychoactive Effects of Oral Dronabinol Studied in a Randomized, Controlled Crossover Clinical Trial for Pain Mohammed A. Issa, MD,*w Sanjeet Narang, MD,*w Robert N. Jamison, PhD,*wz Edward Michna, MD,*w Robert R. Edwards, PhD,*wz David M. Penetar, PhD,wy and Ajay D. Wasan, MD, MSc*wz
Background: Many cannabinoid medications are approved in North America or in phase III trials, such as dronabinol, nabilone, or nabiximols. Little is known about their subjective psychoactive effects when used for pain management. We hypothesized that when used for pain, dronabinol has psychoactive effects in a doseresponse relationship, whose peak effects are comparable with smoking marijuana. Methods: This was a randomized controlled trial of single dose placebo, 10 or 20 mg dronabinol in 30 chronic noncancer pain patients taking opioids and not using marijuana. Participants completed the Addiction Research Center Inventory (ARCI) hourly for 8 hours during 3 monitored sessions. Comparison sample was the ARCI ratings in participants with no pain (N = 20), monitored every 30 minutes after smoking a 1.99% THC (low) and a 3.51% (high strength) marijuana cigarette. Results: The 10 and 20 mg dronabinol doses had significantly elevated scores over time on 4/5 subscales versus placebo (P < 0.05). Average daily morphine use, total pain relief (TOTPAR), age, sex, and baseline pain level were not significant covariates. ARCI peak effects at 2 hours were similar to peak effects of smoked marijuana at 30 minutes (P = 0.80, 10 mg = low strength, 20 mg = high strength). Conclusions: In pain patients, oral dronabinol has similar psychoactive effects to smoking marijuana. This risk must be considered in any decision to prescribe cannabinoid medications for pain. Key Words: cannabinoid, dronabinol, abuse potential, addiction, marijuana
(Clin J Pain 2014;30:472–478)
T
he psychoactive properties of cannabis have been recognized since early times, it remains the most widely used illicit drug globally.1 Despite the possible stigma and legal issues associated with its use, Cannabis sativa has been
Received for publication October 14, 2012; revised November 18, 2013; accepted August 2, 2013. From the Departments of *Anesthesiology, Perioperative, and Pain Medicine; zPsychiatry, Brigham and Women’s Hospital; yBehavioral Psychopharmacology Research Laboratory, McLean Hospital; and wHarvard Medical School, Boston, MA. Supported in part by an investigator-initiated grant from Solvay Pharmaceuticals Inc., Marietta, GA and by grants DA 12014 and DA 00343 from the National Institute on Drug Abuse, Rockville, MD. The authors declare no conflict of interest. Reprints: Mohammed A. Issa, MD, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (e-mail: drissa80@ gmail.com). Copyright r 2013 by Lippincott Williams & Wilkins
472 | www.clinicalpain.com
widely used as a herbal remedy for the treatment of various conditions such as migraine, spasticity, nausea, and vomiting, as well as a number of other disorders.2 The search for the active ingredients of the plant led to the first identification of its main psychoactive ingredient, D-9-tetrahydrocannabinol (THC),3 and the subsequent development of cannabinoid medications. Several cannabinoid medications are currently FDA approved in the United States or in phase III trials, such as dronabinol, nabilone, or nabiximols. Research into their effects continues to be a field of increasing interest, particularly with regard to their use in a variety of therapeutic areas. Dronabinol is an oral synthetic stereoisomer of THC and is currently approved as an appetite stimulant in patients with HIV/AIDS and as a treatment for chemotherapy-induced nausea and vomiting in patients who failed to respond adequately to conventional antiemetic treatments.4 It has been widely studied for a number of other conditions including multiple sclerosis, Parkinson disease and Huntington disease, and disturbed behavior in Alzheimer disease and Tourette syndrome.5 Another area of study is the use of cannabinoid medications for the treatment of persistent intractable pain. With the discovery of the endocannabinoid system and its involvement with analgesia, recent interest has emerged regarding the pain-modulating effects of cannabinoids and the potential of their synergistic analgesic effect with opioids for pain management.6–12 However, such research has not addressed the existing controversy about the psychoactive effects of medicinal cannabinoids when used for pain management, and whether such effects differ from those of the whole marijuana plant. The primary objective of this study was to evaluate the subjective psychoactive effects of oral dronabinol in chronic pain patients on stable doses of opioids, and compare such effects with placebo and smoked marijuana. The Addiction Research Center Inventory (ARCI), a well-validated and reliable measure to assess the subjective effects of certain classes of psychoactive drugs,13 was used as the primary outcome measure for this study. We hypothesized that when used for pain, dronabinol would have psychoactive effects in a dose-response relationship, whose peak effects are comparable with smoking marijuana.
MATERIALS AND METHODS Trial Design The oral dronabinol study was a multidose, randomized, double-blind, placebo-controlled, crossover trial with 3 drug administration sessions conducted at Brigham and Clin J Pain
Volume 30, Number 6, June 2014
Clin J Pain
Volume 30, Number 6, June 2014
Women’s Hospital in the United States. The comparison sample study cohort with smoked marijuana was a 4-visit, randomized-dosing trial conducted separately at McLean Hospital. The dronabinol cohort permitted quantitative determinations of the subjective psychoactive effects, whereas the smoked marijuana cohort allowed for additional qualitative comparisons.
Participants The studies were reviewed and approved by the Institutional Review Boards at Brigham and Women’s Hospital and McLean Hospital, Boston, MA. All participants provided written informed consent before any study-related procedures were performed and were all compensated for their participation in the studies. For the dronabinol group, subjects were compensated $75 for participation in each session. For the smoked marijuana group, subjects were paid $100 for each of the first three smoking study sessions and $150 for the fourth session. They were given a $100 bonus if they finished all four study sessions. Table 1 summarizes the baseline characteristics of the oral dronabinol sample, which has previously been reported in the publication of the analgesic data.10 Thirty chronic noncancer pain participants on opioid therapy were recruited through Brigham and Women’s Hospital. The
TABLE 1. Patient Demographic and Descriptive Characteristics for the Oral Dronabinol Sample (N = 30)
Variables Age (median) 43.5 (± 11.8; range, 21-67) Sex (% Female) 53.3 Race (% white) 96.7 Pain site (% low back) 66.7 Pain duration (% >5 y) 66.7 Opioid duration (% >2 y) 70 Morphine equivalent 68.1 (SD = 57.2; range, 7.5-228) (oral mg/d) Current opioid medication (% of participants) RTC Methadone 30 Morphine—long-acting 30 Oxycodone—long-acting 16.7 PRN Oxycodone—short-acting 36.7 Morphine—short-acting 16.7 Hydrocodone 6.7 Hydromorphone 6.7 Baseline levels Prestudy Diary (0-10) Pain Intensity 6.9 (± 1.3) Pain Relief 3.9 (± 1.7) Pain Bothersomeness (0-4) 2.7 (± 0.6) Satisfaction Baseline (0-10) 3.7 (± 2.0) Brief Pain Inventory Interference with sleep 6.7 (± 3.2) RAND-36 (0-100) Energy/Fatigue 37.1 (± 20.8) Pain 26.6 (± 15.2) Social Functioning 47.8 (± 24.6) HADS Anxiety 6.7 (± 2.9) Depression 6 (± 3.3) HADS indicates Hospital Anxiety and Depression Scale; PRN, as needed; RAND-36, RAND-36-Health Survey; RTC, return to clinic.
r
2013 Lippincott Williams & Wilkins
Subjective Psychoactive Effects of Oral Dronabinol
ages of participants ranged from 21 to 67 years (median age, 43.5 ± 11.8), 53% were female, and the majority selfidentified as white (96.7%). Most participants (66.7%) reported chronic pain >5 years, and low back pain (66.7%) was the most prevalent. The mean morphine equivalent dose per day was 68.1 mg (range, 7.5 to 228.0 mg). Baseline pain intensity was 6.9/10 (± 1.3). Nineteen participants (63.3%) reported using marijuana in the past, 8 of whom reported using within the past year. All participants were required to abstain from use for 1 month before and during enrollment. Participants were also required to have stable opioid analgesic dose for >6 months and report pain of at least 4 on a 0 to 10 numeric rating scale. They were asked to reschedule their visit if their average pain over the past 24 hours was 11 on the Hospital Anxiety and Depression Scale [HADS]); current substance abuse by selfreport and psychosocial history; and any involvement in active litigation, compensation, or disability issues. The comparison cohort consisted of 20 participants with no pain and their ages ranged from 19 to 30 years old (mean age, 21.7 ± 3). Ninety-five percent reported using marijuana 1.6 ± 0.97 times per week, smoked 15.3 ± 4.2 tobacco cigarettes per day, and drank 9 ± 5.6 alcoholic drinks per week. They all showed normal physical examination, electrocardiogram, and clinical laboratory tests before enrollment. They were all current tobacco smokers (average of 10 to 20 cigarettes daily), had no history of drug or alcohol dependence, and no diagnosis of any psychiatric disorders.14
Interventions The aim of this study was to compare the profile of acute effects on subjective measures of dronabinol at 2 doses (10 and 20 mg capsules) with placebo in patients with chronic pain and smoked marijuana (1.99% and 3.51% D9 THC) in those without chronic pain. At the baseline visit for those with chronic pain, enrollment criteria were verified, informed consent was obtained, a history and physical examination were completed, and baseline questionnaires about the participants’ pain, function, and mood were administered. During the 3 treatment sessions, each participant received identically appearing placebo, 10 or 20 mg dronabinol capsules in 1 of 6 randomly allocated sequences. The randomization scheme was generated by the Investigational Drug Service hospital pharmacy, and both study personnel and participants were blinded until all participants had completed the study. The 3 treatment sessions were separated by a minimum of 3 days between each visit. On arrival, participants were asked to complete the ARCI questionnaire and answer questions about their pain and satisfaction levels. These questionnaires were subsequently administered every hour for 8 hours. A symptom checklist www.clinicalpain.com |
473
Clin J Pain
Issa et al
Volume 30, Number 6, June 2014
FIGURE 1. Research design and schema of the oral dronabinol sample.
was administered at the initial and final visits to assess the occurrence of side effects. At the completion of each treatment session, participants were asked to evaluate the blinding process and record their overall satisfaction with the treatment.
Primary Outcome Measure The primary outcome measure of the study was the ARCI. The ARCI is a true/false 49-item well-known, selfrated, well-validated, and reliable measure that can be used to assess the subjective effects of certain classes of psychoactive drugs.13 Elevated scores on its 5 subscales highly correlate with significant psychoactive effects that may potentially increase the likelihood that a substance will be abused in a vulnerable population: the Morphine-Benzedrine Group (MBG, a measure of euphoria and is considered as the hallmark subjective effect of abused drugs), the Benzedrine Group (BG, a measure of stimulant effects relating to intellectual efficacy and energy), the Pentobarbital-Chlorpromazine-Alcohol Group (PCAG, a measure of apathetic sedation), the Amphetamine Scale (A, a measure of amphetamine-like stimulant effects), and the Lysergic Acid Diethylamide (LSD-specific group, a measure of somatic discomfort and dysphoria). Participants were administered the ARCI by paper-and-pencil every hour in the dronabinol group and electronically using a keypad every 30 minutes in the smoked marijuana group.
Study Procedures A comparison sample of those with no pain who smoked marijuana was chosen to contextualize the findings regarding the psychoactive effects of dronabinol in patients with chronic pain. In other words, it was used to illustrate how the effects of dronabinol might compare to smoked cannabis, on a qualitative level primarily. This was a post hoc comparison and, therefore, would not be able to conclusively determine if there were significant differences between groups. As such, despite the statistical limitations in directly comparing cohorts, it was hypothesized that the comparison group
474 | www.clinicalpain.com
would demonstrate similar psychoactive effects to those with chronic pain taking dronabinol. Study procedures in both cohorts were quite similar, and all data were collected in a monitored laboratory environment at individual sessions over the same period of time in 2 hospitals of the Partners Healthcare System (Brigham and Women’s and McLean Hospitals). The comparison sample was a healthy study population with no pain (n = 20), monitored every 30 minutes with the ARCI for 3 hours after smoking a 1.99% THC (low strength) and a 3.51% THC (high strength) marijuana cigarette in random order, at different study sessions. Smoking sessions lasted for 15 minutes, each through a watercooled inhaler device, and participants were monitored continuously for the next 3 hours after smoking. The study visits were separated by a minimum of 3 days between each visit. Participants were required to abstain from all illicit drugs and alcohol for 72 and 24 hours, respectively, before the study. They could not smoke tobacco or have any caffeine from midnight before each study day. Breath samples to check for alcohol and carbon monoxide, as well as urine samples and blood samples (to test for THC and its metabolites, nicotine, cotinine) were collected when participants arrived to the laboratory. Urine drug tests had to be negative for drugs of abuse excluding THC metabolites, or else study visit was rescheduled. If the urine test was positive for THC metabolites, one of the blood samples was tested for the presence of THC and its metabolites to determine if there has been use within the past 72 hours. For more specific details on the experimental design of the comparison study, including the marijuana challenge session, see Penetar et al.14
Statistical Analysis All data were analyzed with Statistical Package for the Social Services (SPSS v 13.0; Chicago, IL). A repeated measures analysis of covariance (ANCOVA) was used to assess hourly and peak subjective responses on the ARCI scales as a primary measurement of dronabinol subjective effects. This was supplemented by an analysis of variance r
2013 Lippincott Williams & Wilkins
Clin J Pain
Volume 30, Number 6, June 2014
comparison between cohorts and doses at the time of peak psychoactive effects. This was determined by the highest mean of 5 ARCI subscale scores in both the cohorts (t = 2 h for the dronabinol group and t = 30 min for the smoked cannabis group). The Tukey corrections were used for multiple dose comparisons within each ARCI subscale for the ANCOVA and peak effects analyses, as each subscale measures a separate construct. Potential covariates that were included in a sensitivity analysis were: age, sex, race, location, type and duration of pain, average morphine equivalent dose and duration of opioid treatment, baseline pain level, baseline HADS score, previous marijuana use, and total pain relief (TOTPAR) reported over the course of the 8-hour sessions in the chronic pain group (TOTPAR). Statistical significance was set at Pr0.05.
RESULTS Dronabinol Versus Placebo Comparisons A repeated measures analysis found that the 10 and 20 mg dronabinol doses resulted in significant changes, relative to placebo, on 4 of the 5 ARCI subscales over time (Fig. 2). Relative to placebo, dronabinol significantly increased MBG (drug effect: F = 5.5; P < 0.05), PCAG (drug effect: F = 8.0; P < 0.01), and Amphetamine (A) (drug effect: F = 3.3; P < 0.05) scores, and decreased BG (drug effect: F = 3.1; P < 0.05) scores. There were no significant differences between the 10 versus 20 mg doses. The overall trends, however, suggest that the 20 mg dose was
Subjective Psychoactive Effects of Oral Dronabinol
associated with the greatest psychoactive effects. BG scores after dronabinol dose were lowest at 2 hours as compared with placebo, indicating a worsening of intellectual energy. For the other subscales, peak effects of the 2 doses of dronabinol versus placebo were also found at 2 hours (P < 0.05 for MBG, PCAG, A, BG, and LSD). The effects of dose on LSD scores were nonsignificant over time (P > 0.05), but the 10 and 20 mg doses were significantly greater than placebo at 2 hours. In the sensitivity analysis, for each of the 3 treatment conditions (placebo, dronabinol 10 and 20 mg), average daily morphine use equivalents, TOTPAR, age, sex, previous marijuana use, and baseline pain level did not show any significant correlations with ARCI effects on any subscale. In a repeated measures ANCOVA analysis, these factors were not significant univariate predictors of ARCI subscale scores; there was neither significant interaction with dose, nor did they significantly alter the F value of dose as a primary predictor of outcome (Fig. 3). In particular, there was no significant relationship between the level of reported pain relief (TOTPAR) and ARCI subscale scores in correlational or ANCOVA analyses, indicating that dronabinol analgesia was reported by the participants as a phenomenon distinct from its psychoactive effects.
Dronabinol Versus Marijuana Smoking Comparisons Peak psychoactive effects of smoked cannabis were found at 30 minutes after completing the inhaling
FIGURE 2. Hourly Addiction Research Center Inventory (ARCI) subscale scores for dronabinol versus placebo. LSD subscale comparisons nonsignificant (not shown). *P < 0.05; **P < 0.01 versus placebo. BG indicates the Benzedrine Group ; LSD, Lysergic Acid Diethylamide; MBC, Morphine-Benzedrine Group; PCAG, Pentobarbital-Chlorpromazine-Alcohol Group. r
2013 Lippincott Williams & Wilkins
www.clinicalpain.com |
475
Issa et al
Clin J Pain
Volume 30, Number 6, June 2014
FIGURE 3. Comparisons of pain intensity differences (TOTPAR) with 10 and 20 mg dronabinol compared with placebo (P < 0.05 and P < 0.01). There were no significant correlation between TOTPAR and Addiction Research Center Inventory (ARCI) effects for each condition. Error bars: ± 2 SE.
procedure. For 3 of the ARCI subscale scores, there were significant differences between the peak psychoactive effects of oral dronabinol (10 or 20 mg at 2 h) and smoked marijuana (low and high dose at 30 min) as compared with placebo (Fig. 4). PCAG (drug effect: F = 5.4; P < 0.05) and LSD (drug effect: F = 3.3; P < 0.05) scores were significantly increased and BG (drug effect: F = 3.5; P < 0.05)
score was significantly decreased in comparison with oral placebo. However, MBG and Amphetamine (A) score differences were not statistically significant (P > 0.05). Peak psychoactive effects of dronabinol 10 and 20 mg at 2 hours were similar to peak effects of low-strength and high-strength smoked marijuana at 30 minutes in all 5 ARCI subscale scores, and there were no statistically significant differences between them (P > 0.45, Fig. 4). Overall, as reported by the participants on the ARCI, the subjective experiences of taking oral dronabinol or smoking marijuana do not appear to be significantly different than each other.
DISCUSSION
FIGURE 4. Peak psychoactive effects of dronabinol 10 or 20 mg versus low or high dose marijuana cigarettes. P-values are all >0.45 for these comparisons. Error bars: ± 2 SE. BG indicates the Benzedrine Group; LSD, Lysergic Acid Diethylamide; PCAG, Pentobarbital-Chlorpromazine-Alcohol Group.
476 | www.clinicalpain.com
This study attempted to assess the subjective psychoactive effects of the cannabinoid medication, dronabinol, when used in combination with stable opioid dosage for pain management, as compared with placebo and smoked marijuana. Results of the study showed that the subjective effects of 10 and 20 mg dronabinol were consistently and significantly greater than placebo on most ARCI subscales and were equivalent to the psychoactive effects of smoking marijuana, although, as expected, it took longer to reach the same peak effects (2 h with oral dronabinol as compared with 30 min with smoked marijuana). These findings imply that in our laboratory environment, dronabinol caused a “high” similar to smoking marijuana when used for pain management. However, this does not necessarily mean that dronabinol has the same abuse liability as marijuana, and other risk factors for addiction should also be considered before concluding that such a risk exists. For instance, the ARCI does not assess drug likability, which is also an important indicator of drug abuse potential. In addition, the results of previous studies assessing the subjective effects and likelihood for abuse and diversion of dronabinol have differed according to the study setting. Several laboratory studies have shown that the subjective effects of smoked marijuana and oral cannabinoids are highly similar in participants who are regular users of r
2013 Lippincott Williams & Wilkins
Clin J Pain
Volume 30, Number 6, June 2014
marijuana and do not have a diagnosis of chronic pain.15–19 Yet, phase IV drug surveillance observational clinical studies carried out primarily in patients with cancer or HIV/AIDS have reported a low abuse potential of such medications. Moreover, a review by Calhoun et al20 found no evidence of abuse or diversion for dronabinol. The authors noted that marijuana users do not value the psychoactive effects of dronabinol because of its slow and gradual onset of action, weak reinforcing effect, and dysphoric feeling. Similar conclusions were also reached with other cannabinoid medications, such as nabilone and nabiximols, with cases of abuse or diversion being rare and only occurring in a very small proportion of recipients.21,22 It is important to recognize the distinct differences between these laboratory and clinical data as they should be interpreted independently. Our study bridges these gaps to some extent. The present study focuses on the subjective effects of dronabinol in a laboratory-based, randomized, double-blinded, multiple dose, crossover trial in a specific patient population with pain, that is, patients with noncancer pain taking prescription opioids. Our results demonstrate that the subjective effects of dronabinol in a laboratory setting are comparable with smoking marijuana, which potentially applies to other oral cannabinoid medications as well in this environment. These laboratory findings may or may not translate clinically to an increased likelihood of dronabinol abuse and/or diversion in this vulnerable patient population (which requires further study). Aside from these considerations, a special aspect in the case of prescribing cannabinoids for chronic pain is the expectation of long-term use and the possible combination with opioid therapy, which may very well increase the abuse liability of both drugs because of their potentially additive addictive properties. In addition, evidence from the National Household Survey on Drug Abuse suggests that the use of marijuana, especially at a young age, can potentially lead to the future use of other illicit substances.23 In our study, although participants were carefully screened before enrollment, THC was found in 4 of the serum samples of chronic pain participants before receiving placebo, which suggests possible illicit use of marijuana by some participants. Therefore, as substance use disorders are already highly prevalent in the chronic pain population,24–26 potential candidates for cannabinoid therapy should be closely selected, educated about, and monitored.27,28 Another important finding in the study was the insignificant relationship between the level of total reported pain relief (TOTPAR) and ARCI subscale scores. This indicates that the psychoactive properties of dronabinol are independent of its synergistic analgesic effects with opioids (reported previously).10 It was believed from early studies that THC could only produce analgesia at doses that were high enough to cause other behavioral side effects. Noyes et al29 compared single doses of placebo and 5,10,15, and 20 mg of THC in 10 cancer pain participants and found significant analgesia with higher doses but at the expense of significant sedation and mental clouding. The first evidence that the antinociceptive effects of THC could be separated from its adverse behavioral effects was presented in 1994, when Smith et al30 demonstrated that a k-opioid receptor antagonist, nor-binaltorphimine (norBNI), blocked only the antinociceptive effect of THC in rodents without altering other pharmacological or behavioral effects. Our study in humans illustrates this phenomenon of separate r
2013 Lippincott Williams & Wilkins
Subjective Psychoactive Effects of Oral Dronabinol
analgesic and psychoactive properties of cannabinoids in a clinical pain patient population. One could argue that the psychoactive effects of dronabinol were amplified by concomitant oral opioid usage in our pain cohort; however, baseline assessment of the study participants did not reveal any patient reports of significant sedation, confusion, impairment, or other cognitive effects of opioids. Nevertheless, this is a potential confounder to generalizing that dronabinol has significant psychoactive effects comparable with smoking marijuana. There are a number of additional limitations worth mentioning in the design of this study. First, the number of participants in each group was limited, and the dronabinol cohort consisted of a heterogenous sample on various doses of opioids. Although this may reflect a typical clinical pain population, future studies with less variability in opioid type and dosage and longer follow-up period are required. Second, the comparison information was collected historically from a previous study that utilized the same primary outcome measure; therefore, between-study variations may have affected our findings. As observed in the methods, we recognize the statistical limitations in directly comparing the dronabinol and smoked marijuana groups. However, these comparisons are still useful qualitatively to illustrate that the psychoactive effects of dronabinol are clinically meaningful. We cannot conclude that the effects of dronabinol and smoked cannabis are equivalent. In addition, only one measure (namely, the ARCI) was used to compare the acute dose effects of oral dronabinol with smoked marijuana, which is not sufficient to give definitive data on a drug’s abuse potential. Thus, additional data from physiological, psychomotor, and cognitive measures should be collected in future studies to better understand the psychoactive effects and abuse liability of oral dronabinol. Further, urine drug testing was not performed before testing in the dronabinol group. We only assessed possible concurrent drug use with self-report, which is a possible confounder to our results. Finally, we did not have an additional comparison group of chronic pain patients who were not taking opioids for pain, as opioids may share several of the subjective and psychoactive effects noted with cannabinoids.31 Despite these limitations, the results of this preliminary study suggest that in chronic pain patients on opioid therapy, dronabinol has similar psychoactive effects to smoking marijuana. This warrants further large-scale observational studies to assess a potential abuse and/or diversion risk. The subjective psychoactive effects of cannabinoids should be considered in any decision to prescribe these medications for chronic noncancer pain. Moreover, our findings have implications for the analgesic development of all medicinal cannabinoids and indicate that these safety issues should be carefully scrutinized in drug development. We were also able to determine that the psychoactive effects of dronabinol are distinct from their analgesic effects. REFERENCES 1. World Drug Report 2011, Cannabis market. Available at: http://www.unodc.org/documents/data-and-analysis/WDR2011/ The_cannabis_market.pdf. Accessed May 30, 2013. 2. Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers. 2007;4:1614–1648. 3. Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86:1646–1647.
www.clinicalpain.com |
477
Issa et al
4. Solvay Pharmaceuticals Inc. Marinols Prescribing Information, 2006. Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2006/018651s025s026lbl.pdf. Accessed May 9, 2013. 5. RotECoDDEAodais-iAf. Assessment of dronabinol and its stereo-isomers. Available at: http://who.int/medicines/areas/ quality_safety/4.2DronabinolCritReview.pdf. Accessed May 30, 2012. 6. Smith FL, Cichewicz D, Martin ZL, et al. The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol. Pharmacol Biochem Behav. 1998;60:559–566. 7. Cichewicz DL, Martin ZL, Smith FL, et al. Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification. J Pharmacol Exp Ther. 1999;289:859–867. 8. Cichewicz DL, McCarthy EA. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003;304:1010–1015. 9. Cichewicz DL. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. 2004;74:1317–1324. 10. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008;9:254–264. 11. Vigano` D, Rubino T, Parolaro D. Molecular and cellular basis of cannabinoid and opioid interactions. Pharmacol Biochem Behav. 2005;81:360–368. 12. Hohmann AG, Suplita RL. Endocannabinoid mechanisms of pain modulation. AAPS J. 2006;8:E693–E708. 13. Fischman MW, Foltin RW. Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict. 1991;86:1563–1570. 14. Penetar DM, Kouri EM, Gross MM, et al. Transdermal nicotine alters some of marihuana’s effects in male and female volunteers. Drug Alcohol Depend. 2005;79:211–223. 15. Hart CL, Haney M, Vosburg SK, et al. Reinforcing effects of oral Delta9-THC in male marijuana smokers in a laboratory choice procedure. Psychopharmacology (Berl). 2005;181: 237–243. 16. Kirk JM, Doty P, De Wit H. Effects of expectancies on subjective responses to oral delta9-tetrahydrocannabinol. Pharmacol Biochem Behav. 1998;59:287–293. 17. Chait LD, Zacny JP. Reinforcing and subjective effects of oral delta 9-THC and smoked marijuana in humans. Psychopharmacology (Berl). 1992;107:255–262.
478 | www.clinicalpain.com
Clin J Pain
Volume 30, Number 6, June 2014
18. Wachtel SR, ElSohly MA, Ross SA, et al. Comparison of the subjective effects of Delta(9)-tetrahydrocannabinol and marijuana in humans. Psychopharmacology (Berl). 2002; 161:331–339. 19. Hart CL, Ward AS, Haney M, et al. Comparison of smoked marijuana and oral delta(9)-tetrahydrocannabinol in humans. Psychopharmacology (Berl). 2002;164:407–415. 20. Calhoun SR, Galloway GP, Smith DE. Abuse potential of dronabinol (marinol). J Psychoactive Drugs. 1998;30:187–196. 21. Ware MA St, Arnaud-Trempe E. The abuse potential of the synthetic cannabinoid nabilone. Addiction. 2010;105: 494–503. 22. Robson P. Abuse potential and psychoactive effects of d-9tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Expert Opin Drug Saf. 2011;10:675–685. 23. SAMHSA Fact sheet: National Household survey on Drug Abuse, 2011. Available at: http://www.samhsa.gov/ data/NSDUH/2k10NSDUH/2k10Results.htm#5.3. Accessed June 6, 2013. 24. Fishbain DA, Rosomoff HL, Rosomoff RS. Drug abuse, dependence, and addiction in chronic pain patients. Clin J Pain. 1992;8:77–85. 25. Maruta T, Swanson DW, Finlayson RE. Drug abuse and dependency in patients with chronic pain. Mayo Clin Proc. 1979;54:241–244. 26. Ready LB, Sarkis E, Turner JA. Self-reported vs. actual use of medications in chronic pain patients. Pain. 1982;12:285–294. 27. Butler SF, Budman SH, Fernandez K, et al. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain. 2004;112:65–75. 28. Butler SF, Budman SH, Fernandez KC, et al. Development and validation of the Current Opioid Misuse Measure. Pain. 2007;130:144–156. 29. Noyes R, Brunk SF, Baram DA, et al. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol. 1975;15: 139–143. 30. Smith PB, Welch SP, Martin BR. Interactions between delta 9tetrahydrocannabinol and kappa opioids in mice. J Pharmacol Exp Ther. 1994;268:1381–1387. 31. Zacny JP, Gutierrez S. Subjective, psychomotor, and physiological effects profile of hydrocodone/acetaminophen and oxycodone/acetaminophen combination products. Pain Med. 2008;9:433–443.
r
2013 Lippincott Williams & Wilkins
